Endoscopic management of recurrent tracheoesophageal fistula induced by chronic use of nonsteroidal anti-inflammatory drugs: A case report and review of the literature.

Tracheoesophageal fistula (TEF) is frequently congenital and requires surgical correction. TEF can also occur secondary to malignant esophageal tumors or benign diseases and these cases are managed by endoscopic means, such as closing the defect with metallic stents. Although esophageal injury can occur secondary to nonsteroidal anti-inflammatory drugs (NSAIDs), TEF secondary to chronic NSAIDs use has not been described in the literature. We report the case of a male patient with refractory migraine and chronic use of NSAIDs, with a history of esophageal stenosis presenting with acute-onset total dysphagia. Upper gastrointestinal endoscopy and CT-scan revealed TEF located at 25 cm from the incisors. An esophageal stent was placed endoscopically, and 6 weeks a second stent was placed in a stent-in-stent manner to allow removal of both stents. Endoscopic control after the removal of the stents showed the persistence of the fistula, so a third stent was placed as a rescue therapy. Against medical advice, the patient continued to use OTC painkillers and NSAIDs in large doses. Three months later, he was readmitted with total dysphagia and recent-onset dysphonia. CT scan revealed a new fistula above the already placed stent. A second metallic stent was endoscopically placed through the old stent to close the newly developed fistula. The patient was discharged on the third day with no complications and he remains well at 6 months follow-up. Due to small cases studies, recurrent TEF remains a therapeutic challenge. Endoscopic therapy is usually an effective solution, but complex cases might require multiple treatment sessions.

Bevacizumab-induced tracheoesophageal fistula in a patient suffering from lung cancer with bulky subcarinal lymph node: a case report.

A 66-year-old male with advanced non-small-cell lung cancer (NSCLC) who was previously treated with carboplatin, pemetrexed, and bevacizumab consequently suffered from severe coughing during deglutition. Chest computed tomography (CT) revealed a tracheoesophageal fistula (TEF) between the left main bronchus and esophagus through a subcarinal metastatic lymph node. Given the extreme swelling of the lymph node due to metastatic cancer, it was determined that the walls of the bronchus and esophagus had been injured simultaneously. Delayed and dysfunctional wound healing due to bevacizumab resulted in necrosis of the contact region leading to fistula formation. This case suggests that using bevacizumab for NSCLC in patients with bulky subcarinal lymphadenopathy may increase the risk for TEF.

Impaired VEGF Signaling in Lungs with Hypoplastic Esophageal Atresia and Effects on Branching Morphogenesis.

BACKGROUND/AIMS: Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often suffer chronic respiratory tract disease. We previously reported that primary lung maldevelopment caused by deficient branching of embryonal airways in experimental EA-TEF was induced by Adriamycin. In this study, we investigated the Vascular endothelial growth factor (VEGF) pathway in the developing lung in an EA-TEF rat model. We further analyzed the effect of recombinant VEGF treatment in vitro on branching morphogenesis of embryo lungs in experimental EA-TEF. METHODS: Pregnant rats received either Adriamycin or vehicle on E7, E8 and E9. Lungs were recovered at E15, E18 and E21. Expression of VEGF and receptors (Flk-1 and Flt-1) were assessed by quantitative PCR, immunohistochemistry and immunoblotting. E13 lungs were cultured for 72 hours with 50 ng/mL of recombinant rat VEGF in serum-free medium. The rates of increase in bud count and airway contour were evaluated. RESULTS: Our results showed a significant downregulation of VEGF during pseudoglandular and canalicular stages. In contrast, there were significantly higher levels of the Flt-1 receptor in the canalicular stage, which may represent a compensatory response to decreased VEGF. However, both variables returned to normal levels at the saccular stage. Exogenous VEGF treatment enhanced hypoplastic lung growth, evidenced by the increase in bud count and airway contour. CONCLUSIONS: A VEGF signaling defect possibly plays an important role in defective embryonic airway branching. Additionally, VEGF treatment may accelerate lung growth in EA-TEF lungs.

Diethylstilbestrol (DES): also harms the third generation.

Diethylstilbestrol(DES) is a synthet- ic nonsteroidal oestrogen and endo- crine disruptor that was used in the 1950s-1970s to prevent spontaneous abortion, despite its lack of proven efficacy. Millions of women worldwide took DES during pregnancy. In France, between 1951 and 1981, about 160 000 children were exposed to DES during the first trimester of their intrauterine life, and in some cases almost throughout the entire pregnancy. They are referred to as "DES daughters" and "DES sons". In 2010, in France, about 25 000 DES daughters were aged 33 to 40 years: pregnancies among these women are foreseeable until about 2020. In utero exposure to DES can have harmful effects. In particular, DES daughters have an increased risk of cancer and structural abnormalities of the uterus that can adversely affect their pregnancies. What are the consequences of tak- ing DES during pregnancy for the third generation, i.e. the children of DES children? To answer this question, we reviewed the available data in mid- 2016 using the standard Prescrire methodology. According to a retrospective study conducted in France by Réseau DES France, published in 2016, which included 4409 DES grandchildren (2228 girls and 2181 boys) and about 6000 controls, about one-quarter of DES grandchildren are born prematurely. Preterm delivery exposes neonates to serious neonatal complications, including neurosensory disorders, disabilities and increased neonatal mor- tality. The more premature the baby, the greater the risk of complications. In the Réseau DES France study, cerebral palsy was more frequent in the DES grandchildren group: 59/10 000, versus 6/10 000 in the control group. A study conducted in the United States in about 4500 DES daughters found that preterm delivery occurred at a frequency of about 26%, much higher than that reported in controls. Neonatal mortality was 8 times higher among DES grandchildren, and the risk of stillbirth was twice as high. Other smaller studies have also shown an increased risk of preterm birth. A cohort study conducted in about 5000 DES grandchildren found that the risk of malformations of any type was higher than in the unexposed control group. Epidemiological studies, conduct- ed in several countries, found an increased frequency of hypospadias in DES grandsons. The relative risk was about 5 in the largest study. Other, less robust studies found no statistically significant difference. Several studies in several countries have shown a twofold increase in the risk of oesophageal atresia or tracheo- oesophageal fistula in DES grandchildren. The data on congenital heart defects or musculoskeletal malformations are limited and uninformative. Epidemiological studies have not identified a significant increase in the risk of gynaecological anomalies or cancers in DES granddaughters. Limited data are available on the risk of malformations in the children of DES sons. The data obtained in rodents exposed to DES (and other endocrine disruptors) make it entirely plausible that in utero exposure to DES, in humans too, provokes epigenetic effects that are passed on to future generations not directly exposed to DES. In practice, these data should be discussed with DES daughters, their partners and healthcare teams so that appropriate monitoring, clinical man- agement and follow-up can be arranged for both mother and baby. The harms of taking DES during pregnancy last for decades and affect future generations.

Lung maturity in esophageal atresia: Experimental and clinical study.

INTRODUCTION: Esophageal atresia and tracheoesophageal fistula (EA-TEF) survivors suffer respiratory morbidity of unclear pathogenesis. Defective lung morphogenesis has been described in the rat model. This study examined fetal lung growth and maturity in rats and patients with EA-TEF. METHODS: Pregnant rats received either adriamycin or vehicle. Control and adriamycin-exposed lungs, with and without EA-TEF, were weighed and processed for RT-PCR, DNA quantification, immunofluorescence and immunoblot analysis of TTF1, VEGF, Sp-B, and α-sma. Twenty human lungs were also processed for immunofluorescence and Alcian-blue staining. RESULTS: Lungs from fetuses with EA-TEF (E21) showed decreased total DNA; FGF7 and TTF1 mRNA expressions were upregulated at E15 and E18, respectively. Protein expression and immunofluorescent distribution of maturity markers were similar. Lungs from stillborns with EA-TEF showed decreased epithelial expression of Sp-B and VEGF whereas those from newborns tended to have less Sp-B and more VEGF and mucous glands. DISCUSSION: The lungs of rats with EA-TEF were hypoplastic but achieved near-normal maturity. Stillborns with EA-TEF exhibited an apparently disturbed differentiation of the airway epithelium. Newborns with EA-TEF demonstrated subtle differences in the expression of differentiation markers, and increased number of mucous glands that could influence postnatal respiratory adaptation and explain some respiratory symptoms of EA-TEF survivors.

Tracheoesophageal fistula in adults due to corrosive ingestion: challenges in management.

Esophagorespiratory fistula in adults as a result of corrosive ingestion is a rare occurrence and is a difficult problem to manage. Three young (15-19 years) patients (2F, 1M) out of 115 (incidence 2.6%) of corrosive ingestion who had tracheoesophageal fistula (TEF) were reviewed retrospectively. After initial management, enteral route of nutrition was established. Based on the extent of concomitant esophageal stricture, the fistulae were classified as: type I (short) and type II (long segment). Fistula was repaired through thoracotomy and formation of a neomembranous trachea. Esophageal stricture could be managed either short-segment resection (type I) or resection and replacement (type II). The etiology was aluminum phosphide in two and caustic soda in one. All the patients were operated beyond 9 weeks of ingestion. Tracheal defect was 5, 9 and 30 mm. Fistula could be repaired by neomembranous trachea in all the patients and defect reinforced with pleural flap in two and intercostal muscle flap in one patient. Two patients required colon interposition, while one could be managed with short-segment resection. All the patients are well at follow-up. TEF due to corrosive ingestion is a rare entity in adults. Formation of a neomembranous trachea is feasible in all patients. Management of esophageal stricture depends upon the pattern of involvement of the esophagus.

Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer.

BACKGROUND: In the past decade, targeted therapy with antiangiogenic drugs has become standard of care for most types of metastatic, progressive thyroid cancer. While these drugs were thought initially to be less toxic than traditional chemotherapy, they can have rare but serious and fatal toxicities. Once such toxicity that has been reported in other tumor types is upper airway fistula formation, which can be life-threatening. SUMMARY: Here, we describe three patients treated with antiangiogenic tyrosine kinase inhibitors at two academic institutions who developed aerodigestive fistula. All three patients had risk factors for fistula formation, which included external beam radiation and/or large tumor with invasion of the tracheal wall. CONCLUSIONS: Fistula formation is a known but rare side effect of antiangiogenic tyrosine kinase inhibitors. Knowledge of the risk factors that may predispose thyroid cancer patients to this serious adverse event is vital prior to prescribing antiangiogenics. Particular caution should be observed when using these drugs in patients undergoing radiation therapy or surgery, or in patients whose tumor is invading vital structures of the neck, as they may be at higher risk of developing this rare complication. In these patients, antiangiogenic tyrosine kinase inhibitors should be used cautiously, patients should be aware of the risk, and physicians should monitor patients for symptoms of fistula.

Maternal hyperthyroidism increases the prevalence of foregut atresias in fetal rats exposed to adriamycin.

PURPOSE: Gastrointestinal malformations such as esophageal atresia with tracheoesophageal fistula (EA/TEF) and duodenal atresia (DA) have been reported in infants born to hyperthyroid mothers or with congenital hypothyroidism. The present study aimed to test whether maternal thyroid status during embryonic foregut division has any influence on the prevalence of EA/TEF and DA in an accepted rat model of these malformations. METHODS: Pregnant rats received either vehicle or 1.75 mg/kg i.p. adriamycin on gestational days 7, 8 and 9. Transient maternal hyper or hypothyroidism was induced by oral administration of levothyroxine (LT4, 50 µg/kg/day) or propylthiouracil (PTU, 2 mg/kg/day), respectively, on days 7 to 12 of gestation. Plasma cholesterol, total T3, free T4 and TSH were measured at gestational days 7, 12, and 21. At the end of gestation, the mothers were sacrificed and embryo-fetal mortality was recorded. Fetuses were dissected to determine the prevalence of esophageal and intestinal atresias. RESULTS: At gestational day 12, mothers treated with LT4 or PTU had hyper or hypothyroid status, respectively; plasma cholesterol levels were similar. In the adriamycin-exposed fetuses from hyperthyroid mothers, the embryonal resorption rate and the prevalence of both EA/TEF and DA were significantly higher than in the other groups; maternal hypothyroidism during the same period did not have significant effect on the prevalence of atresias. CONCLUSIONS: Maternal hyperthyroidism during the embryonic window corresponding to foregut cleavage increased the prevalence of both EA/TEF and duodenal atresia in fetal rats exposed to adriamycin. This suggests that maternal thyroid hormone status might be involved in the pathogenesis of foregut atresias and invites further research on this likely clinically relevant issue in humans.

Altered Tbx1 gene expression is associated with abnormal oesophageal development in the adriamycin mouse model of oesophageal atresia/tracheo-oesophageal fistula.

INTRODUCTION: Oesophageal atresia/tracheo-oesophageal atresia (OA/TOF) frequently arises with associated anomalies and has been clinically linked with 22q11 deletion syndromes, a group of conditions due to Tbx1 gene mutation which include Di George syndrome. Tbx1 and Tbx2 genes modulate pharyngeal and cardiac development, but are also expressed in the developing foregut and are known to interact with key signalling pathways described in oesophageal formation including bone morphogenic proteins. The adriamycin mouse model (AMM) reliably displays OA/TOF-like foregut malformations providing a powerful system for investigating the disturbances in gene regulation and morphology involved in tracheo-oesophageal malformations. We hypothesised that foregut abnormalities observed in the AMM are associated with altered Tbx1 and Tbx2 gene expression. METHODS: Time-mated CBA/Ca mice received intra-peritoneal injection of adriamycin (for treated) or saline (for controls) on embryonic days (E)7 and 8. Untreated Cd1 embryos were used to establish normal expression patterns. Embryos harvested on E9-E11 underwent whole-mount in situ hybridization with labelled RNA probes for Tbx1 and Tbx2. Optical projection tomography was used to visualise expression in whole embryos by 3D imaging. RESULTS: Tbx1 expression was visualised in a highly specific pattern in the proximal oesophageal endoderm in normal and control embryos. In the AMM, extensive ectopic expression of Tbx1 was detected in the dorsal foregut and adjacent to the TOF. The focally restricted oesophageal expression pattern persisted in the AMM, but was posteriorly displaced in relation to the tracheal bifurcation. Tbx2 was widely expressed in the ventral foregut mesoderm of controls, lacking specific endoderm localisation. In the AMM, altered Tbx2 expression in the foregut was only seen in severely affected embryos. CONCLUSION: Highly specific Tbx1 expression in the proximal oesophageal endoderm suggests that Tbx1 may be an important regulator of normal oesophageal development. Altered Tbx1 expression in dorsal foregut and adjacent to the TOF in the AMM suggests that Tbx1 gene disruption may contribute to the pathogenesis of tracheo-oesophageal malformations.

Formic acid poisoning in a tertiary care center in South India: A 2-year retrospective analysis of clinical profile and predictors of mortality.

BACKGROUND: Formic acid (FA), a common industrial compound, is used in the coagulation of rubber latex in Kerala, a state in southwestern India. Easy accessibility to FA in this region makes it available to be used for deliberate self-harm. However, the literature on intentional poisoning with FA is limited. STUDY OBJECTIVES: To determine the patterns of presentation of patients with intentional ingestion of FA and to find the predictors of mortality. A secondary objective was to find the prevalence and predictors of long-term sequelae related to the event. METHODS: We performed a 2-year chart review of patients with acute intentional ingestion of FA. Symptoms, signs, outcomes and complications were recorded, and patients who survived the attempt were followed-up by telephone or personal interview to identify any complications after their discharge from the hospital. RESULTS: A total of 302 patients with acute formic acid ingestion were identified during the study period. The mortality rate was 35.4% (n = 107). Bowel perforation (n = 39), shock (n = 73), and tracheoesophageal fistula (n = 4) were associated with 100% mortality. Quantity of FA consumed (p < 0.001), consuming undiluted FA (p < 0.001), presenting symptoms of hypotension (p < 0.001), respiratory distress (p < 0.001), severe degree of burns (p = 0.020), hematemesis (p = 0.024), complications like metabolic acidosis (p < 0.001) and acute respiratory distress syndrome (p < 0.001) were found to have significant association with mortality. The prevalence of esophageal stricture (n = 98) was 50.2% among survivors and was the most common long-term sequela among the survivors. Stricture was significantly associated with hematemesis (p < 0.001) and melena (p < 0.001). CONCLUSION: This study highlights the magnitude and ill-effects of self-harm caused by a strong corrosive, readily available due to very few restrictions in its distribution. Easy availability of FA needs to be curtailed by enforcing statutory limitations in this part of the world. Patients with hematemesis or melena after FA ingestion may be referred for early dilatation therapy in a setting where emergency endoscopic evaluation of all injured patients is not practical.

Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial.

PURPOSE: Bevacizumab and erlotinib have been shown to improve survival in stage IV non-small-cell lung cancer (NSCLC). This phase I/II trial was designed to incorporate these agents with induction and concurrent chemoradiotherapy in stage III NSCLC. PATIENTS AND METHODS: Patients received induction chemotherapy (carboplatin area under the curve [AUC] 6, paclitaxel 225 mg/m(2), and bevacizumab 15 mg/kg on days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly with bevacizumab 10 mg/kg every other week for four doses) and thoracic conformal radiation therapy (TCRT) to 74 Gy. In the phase I portion, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, Tuesday through Friday, during TCRT. Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3 to 6 weeks later for six cycles. RESULTS: Forty-five eligible patients were enrolled. The objective response rates to induction and overall treatment were 39% (95% CI, 24% to 55%) and 60% (95% CI, 44% to 75%), respectively. The median progression-free and overall survival times were 10.2 months (95% CI, 8.4 to 18.3 months) and 18.4 months (95% CI, 13.4 to 31.7 months), respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with one patient with grade 3 tracheoesophageal fistula), which was often prolonged. Consolidation therapy with bevacizumab and erlotinib was not feasible. CONCLUSION: The use of bevacizumab and erlotinib as administered in this trial is not recommended given the lack of an efficacy signal and the substantial risk of esophageal toxicity.

The effect of adriamycin exposure on the notochord of mouse embryos.

The notochord has important structural and signaling properties during vertebrate development with key roles in patterning surrounding tissues, including the foregut. The adriamycin mouse model is an established model of foregut anomalies where exposure of embryos in utero to the drug adriamycin leads to malformations including oesophageal atresia and tracheoesophageal fistula. In addition to foregut abnormalities, treatment also causes branching, displacement, and hypertrophy of the notochord. Here, we explore the hypothesis that the notochord may be a primary target of disruption leading to abnormal patterning of the foregut by examining notochord position and structure in early embryos following adriamycin exposure. Treated (n = 46) and control (n = 30) embryos were examined during the crucial period when the notochord normally delaminates away from the foregut endoderm (6-28 somite pairs). Transverse sections were derived from the anterior foregut and analyzed by confocal microscopy following immunodetection of extracellular matrix markers E-cadherin and Laminin. In adriamycin-treated embryos across all stages, the notochord was abnormally displaced ventrally with prolonged attachment to the foregut endoderm. While E-cadherin was normally detected in the foregut endoderm with no expression in the notochord of control embryos, treated embryos up to 24 somites showed ectopic notochordal expression indicating a change in characteristics of the tissue; specifically an increase in intracellular adhesiveness, which may be instrumental in structural changes, affecting mechanical and signaling properties. This is consistent with disruption of the notochord leading to altered signaling to the foregut causing abnormal patterning and congenital foregut malformations.

Choanal atresia associated with tracheoesophageal fistula: the spectrum of carbimazole embryopathy.

This article focuses on the case of a newborn infant boy with bilateral choanal atresia, tracheoesophageal fistula, and bilateral fifth-finger clinodactyly. This infant had been exposed to carbimazole in utero during the treatment of maternal Graves disease. Teratogenic defects caused by carbimazole were recently recognized, and their phenotypes have been defined. Choanal atresia, esophageal atresia, athelia or hypothelia, developmental delay, hearing loss, and dysmorphic facial features have all been reported. To our knowledge, this is the first documented case of tracheoesophageal fistula without esophageal atresia (H type). Knowledge of the teratogenic potential of carbimazole is important when managing Graves disease in women of childbearing age.

Grade 1 microtia, wide anterior fontanel and novel type tracheo-esophageal fistula in methimazole embryopathy.

Carbimazole (CMZ) and its active metabolite methimazole (MMI) are antithyroid medications, which can result in MMI/CMZ embryopathy in susceptible individuals. The incidence of birth defects related to MMI/CMZ embryopathy remains unclear as several epidemiologic studies failed to prove a correlation, despite positive case-control studies and numerous case reports. Malformations reported in exposed individuals and commonly recognized as MMI/CMZ embryopathy include cutis aplasia of the scalp, choanal atresia, esophageal atresia (EA), tracheo-esophageal fistula (TEF), persistent vitelline duct, athelia/hypothelia, and subtle facial dysmorphisms including sparse or arched eyebrows. Here, we report on individuals with early pregnancy exposure to MMI, with microtia and various other anomalies associated with MMI embryopathy, suggesting that microtia is also seen with increased frequency after prenatal MMI exposure. Additional unusual malformations among our patients include a previously unreported type of TEF with three separate esophageal pouches and a fistula connecting the middle pouch to the trachea in one child, and absence of the gall bladder in another. An enlarged anterior fontanel was seen in three patients, and clinodactyly of the fifth finger was noted in three. The similarities between our three patients with microtia after MMI exposure and the two previously reported with microtia after CMZ exposure support the concept of microtia being related to the MMI/CMZ exposure. Recognition of microtia as a manifestation of MMI/CMZ embryopathy will likely increase the number of diagnosed cases and thus affect ascertainment. We propose diagnostic criteria for MMI/CMZ embryopathy, including the presence of at least one major characteristic finding.

Tracheoesophageal fistula secondary to chemical trauma: is there a place for planned conservative management?

OBJECTIVE: We present a unique case in which closure of a large tracheoesophageal fistula was achieved with planned conservative management. METHOD: The literature was reviewed for other documented cases of spontaneous closure of traumatic tracheoesophageal fistula. RESULTS: Acquired tracheoesophageal fistula may result secondary to a chemical burn from an alkaline disc battery impacted in the oesophagus, particularly when the presentation, and thus diagnosis, are delayed. This condition is rare. The majority of such cases occur in children, and are conventionally managed with surgical repair. We found only three previously reported cases in which conservative management was attempted. CONCLUSION: Non-interventional management should be tried initially for the management of paediatric acquired tracheoesophageal fistula, to permit closure by secondary intention.

Mesenchymal expression of Tbx4 gene is not altered in Adriamycin mouse model.

PURPOSE: The Adriamycin mouse model (AMM) is a reproducible teratogenic model of esophageal atresia/tracheo-esophageal fistula (EA/TEF). Tbx4 is a member of the T-box family of transcription factor genes, which is reported to play a key role in separation of the respiratory tract and the esophagus. Up-regulation of Tbx4 is reported to cause TEF in the chick. Optical projection tomography (OPT) is a technique that allows three-dimensional (3D) imaging of gene expression in small tissue specimens in an anatomical context. The aim of this study was to investigate the temporo-spatial expression of Tbx4 during the critical period of separation of the trachea and esophagus in normal and Adriamycin treated embryos using OPT. MATERIALS AND METHODS: Time-mated CBA/Ca mice received intraperitoneal injections of Adriamycin (6 mg/kg) or saline on days 7 and 8 of gestation. Embryos were harvested on days 9-12, stained following whole mount in situ hybridization with labeled RNA probes to detect Tbx4 transcripts (n = 5 for each treatment/day of gestation). Immunolocalization with the endoderm marker Hnf3beta was used to visualize morphology. Embryos were scanned by OPT to obtain 3D representations of gene expression domains. Animal licence no. B100/4106. RESULTS: OPT elegantly revealed Tbx4 gene expression in both controls and in the disorganized pulmonary mesenchyme in the treated embryos. Although characteristic morphological abnormalities were observed in Adriamycin treated embryos, there was no significant difference in Tbx4 transcript distribution around lung primordia in comparison with control embryos. CONCLUSION: Although previously reported morphological abnormalities of notochord and esophagus were observed in AMM, Tbx4 gene expression was unaltered, suggesting that esophageal anomalies can occur in the presence of normal Tbx4 gene expression in this model.